tan-67 and Substance-Withdrawal-Syndrome

As a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA.. To study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia.. We created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice.. DORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal.

Topics: Analgesics; Analgesics, Opioid; Animals; Ethanol; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naltrexone; Narcotic Antagonists; Pain Management; Quinolines; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome

Alcoholism and anxiety disorders have a huge impact on society and afflict 17.6 million and 40 million people in the United States, respectively. A strong comorbidity exists between alcoholism and anxiety disorders. Indeed, alcohol withdrawal-induced anxiety is a primary contributing factor for relapse, and anxiolytics are a common adjuvant therapy prescribed for treatment-seeking alcoholics. It is thought that the use of alcohol to self-medicate and relieve anxiety contributes to the development of addiction. Treatment for anxiety disorders and alcoholism exist but are not universally effective. The delta opioid receptor (DOR) plays a role in both alcohol consumption and anxiety, making it a very interesting clinical target. Two pharmacologically distinct DORs have been described: DOR1 and DOR2. We find here that the relative specificity of DOR agonists for DOR1 or DOR2 can greatly affect the effects they exert on ethanol consumption and anxiety. The DOR1 agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,30g]isoquinoline (TAN-67), although not effective in decreasing anxiety-like behavior in naive mice, has anxiolytic-like properties in ethanol-withdrawn mice. In contrast, a less subtype-selective agonist, (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), while also reducing anxiety-like behavior, increases ethanol consumption. In addition, we found that the conical anxiolytic diazepam [DZ; 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one] is a less effective anxiolytic in ethanol-withdrawn mice than in naive mice. Together, our findings suggest that selective DOR agonists can decrease anxiety-like behavior and are more effective than diazepam at reducing ethanol consumption. We believe the dual efficacy of DOR1 agonists makes these receptors an interesting therapeutic target for treatment-seeking alcoholics.

Topics: Alcohol Deterrents; Alcohol Drinking; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Benzamides; Diazepam; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Naltrexone; Narcotic Antagonists; Piperazines; Quinolines; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid, delta; Substance Withdrawal Syndrome

Several lines of evidence indicate that central opioid systems may be involved in the behavioral effects of nicotine. We previously reported that mecamylamine-precipitated nicotine-withdrawal aversion can be evaluated using the conditioned place preference paradigm.. In the present study, modulation of opioidergic systems in mecamylamine-precipitated nicotine-withdrawal aversion was investigated.. Male Sprague-Dawley rats were chronically treated s.c. with 10 mg/kg/day (-)-nicotine tartrate using an osmotic minipump. After nicotine treatment for 7 days, conditioning sessions were performed. In the morning, the rats were treated with mecamylamine (0.3-3.0 mg/kg, s.c.), hexamethonium (1.0-3.0 mg/kg, s.c.), naloxone (0.1-1.7 mg/kg), or saline (1.0 ml/kg, s.c.) in one compartment for 60 min. In the evening of the same day, rats were treated with the other treatments and confined to the other compartment for 60 min. Rats were treated with morphine (3.0 mg/kg, s.c.) or TAN-67 (56.0 mg/kg, s.c.) 30 min prior to mecamylamine injection in the conditioning session. On the next day of conditioning, tests were performed.. Mecamylamine, which is known to pass the blood-brain barrier, produced a dose-dependent place aversion. However, hexamethonium, which fails to penetrate the blood-brain barrier, failed to produce a place aversion. Mecamylamine-precipitated nicotine-withdrawal aversion was significantly attenuated by pretreatment with the mu-opioid receptor agonist morphine and the highly selective delta-opioid receptor agonist TAN-67, which was administered 30 min before mecamylamine injection in the conditioning session. Moreover, naloxone at doses (0.1-1.7 mg/kg) that alone failed to show a place aversion in non-treated rats, produced a dose-dependent place aversion in rats that had been chronically treated with nicotine.. These results suggest that central opioid systems may be involved in nicotine-withdrawal aversion.

Topics: Analgesics; Animals; Male; Mecamylamine; Naloxone; Narcotic Antagonists; Nicotine; Nicotinic Antagonists; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Substance Withdrawal Syndrome